Immediate release dosage form

ABSTRACT

An improved immediate release solid dosage form of naproxen with a certain particle size distribution for the intragranular portion, and a certain particle size distribution for the carbonate portion that allows naproxen to remain in solution and achieves fast dissolution and fast absorption of naproxen. The invention provides a naproxen dosage form that when administered to a human in a fasted state provides an average blood plasma naproxen concentration of at least 15-20 μg/ml in 10 minutes or less. The invention also provides a naproxen dosage form that when administered to a human in a fed state provides an average blood plasma naproxen concentration of at least 15-20 μg/ml in 50 minutes or less.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 16/364,244filed on Mar. 26, 2019, the complete disclosure of which is herebyincorporated herein by reference for all purposes.

The present invention relates to a novel immediate release solid dosageform which achieves fast dissolution and fast absorption of naproxen inhumans.

BACKGROUND OF INVENTION

Naproxen is a propionic acid derivative. It is a nonsteroidalanti-inflammatory drug and a potent inhibitor of the cyclooxygenaseresponsible for the biosynthesis of prostaglandins Naproxen hasanti-inflammatory, analgesic and antipyretic activity in man. Naproxenand salts of naproxen are indicated for the reduction of fever and thetreatment of pain, e.g. arthritis pain, pain of inflammation, muscularache, backache, headache, migraine pain, pain of menstrual cramps,toothache, and pains associated with common cold.

Davies and Anderson, Clinical Pharmacokinetics, 32(4):268-93 (1997)reports that following oral administration, naproxen is rapidly andcompletely absorbed, and the extent of absorption results in similarexposure, as measured by area under the concentration-time curve,compared with intravenous administration. The rapidity but not theextent of absorption is affected by the presence of food in the stomach.Maximum plasma concentration is typically achieved within 1-2 hoursafter administration of naproxen sodium.

Speed to the onset of pain relief is an important unmet need in the paincare space. Improving the rate and extent of absorption of oralformulations of compounds has been and continues to be researched. Oncean immediate release solid swallow composition reaches the stomach, itundergoes disintegration and/or dissolution and passes into the smallintestine where the active ingredient is absorbed across the intestinalwalls into the circulatory system via the portal vein and liver beforereaching the site of action. For drugs where absorption is not ratelimited, such as naproxen, fast disintegration and fast dissolution ofthe active ingredient will promote fast absorption in vivo. U.S. Pat.No. 9,757,455 (Roberts et. al) discloses formulations manufactured asimmediate release solid dosage forms intended to be swallowed intact,which achieve fast dissolution and fast absorption of an activeingredient, including naproxen.

However, naproxen does have pH related solubility. In pH above 5.4,naproxen stays in solution. At lower acidic pH conditions, naproxensodium dissolves but immediately precipitates out into a fine colloidalparticulate matter of naproxen. If naproxen precipiates in the stomach,the naproxen must pass into the small intestine before it solubilizesand re-dissolves. This may create a delay in absorption.

Patent application publication US20070134317 describes this phenomenonand discloses a non-effervescent form of sodium naproxen comprisingsodium hydrogen carbonate. It describes the formation of agglomerates ofprecipitated naproxen to larger, poorly soluble naproxen crystalagglomerates, and proposes formulations to minimize potential poorsolubility and bioavailability.

Applicants have now discovered an improved immediate release soliddosage form with a certain particle size distribution for theintragranular portion, and a certain particle size distribution for thecarbonate portion which allows for naproxen to remain in solution andachieves faster dissolution and faster absorption of naproxen in humans.In particular, applicants have discovered a naproxen dosage form thatwhen administered to a human in a fasted state provides an average bloodplasma naproxen concentration of at least 15-20 μg/ml in 10 minutes orless. Applicants have further discovered a naproxen dosage form thatwhen administered to a human in a fed state provides an average bloodplasma naproxen concentration of at least 15-20 μg/ml in 50 minutes orless for compositions comprising 300 mg to 500 mg of a carbonatecompound. Applicants have further discovered a naproxen dosage form thatwhen administered to a human in a fed state provides an average bloodplasma naproxen concentration of at least 15-20 μg/ml in 25 minutes orless for compositions comprising 500 mg of a carbonate compound.

SUMMARY OF THE INVENTION

The present invention provides an improved immediate release soliddosage form of naproxen sodium that achieves fast dissolution in thestomach, allows naproxen to remain in solution and achieves fastabsorption of naproxen. Particularly, the present invention provides anaproxen sodium dosage form that when administered to a human in afasted state provides an average blood plasma naproxen concentration ofat least 15-20 μg/ml in 10 minutes or less. The present invention alsoprovides a naproxen dosage form that when administered to a human in afed state provides an average blood plasma naproxen concentration of atleast 15-20 μg/ml in 50 minutes or less for compositions comprising 300mg to 500 mg of a carbonate compound. The present invention alsoprovides a naproxen dosage form that when administered to a human in afed state provides an average blood plasma naproxen concentration of atleast 15-20 μg/ml in 25 minutes or less for compositions comprising 500mg of a carbonate compound.

In one embodiment, the immediate release solid dosage form of naproxensodium has an intragranular particle size distribution of about 200-400microns. In another embodiment, the immediate release solid dosage formof naproxen has a carbonate particle size distribution of about 50-200microns.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings described herein are for illustrative purposes only ofselected embodiments, and are not intended to limit the scope of thepresent disclosure.

FIG. 1 depicts the mean naproxen concentration time profiles underfasted conditions for the study described in Examples 1 and 2.

FIG. 2 depicts the mean naproxen concentration time profiles under fedconditions for the study described in Examples 1 and 2.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention is directed to the use of a composition whichdelivers a time to a specific average blood plasma (therapeutic)concentration in mammalian subjects which correlates to pain relief.This minimum effective therapeutic plasma concentration (MEC) fornaproxen is defined herein as between 15 to 20 μg/mL. In one embodimentthis is regarded as administration in a fasted condition with aresulting time to the MEC of a range of 7 minutes to 9 minutes. In oneembodiment the time to MEC in a fasted condition is less than 20minutes, or less than 15 minutes, or less than 10 minutes. In anotherembodiment the time to minimum effective therapeutic concentration in afed condition is in a range of 15 minutes to 25 minutes. In anotherembodiment, the time to MEC in a fed condition is less than 50 minutes,or less than 40 minutes, or less than 35 minutes, or less than 30minutes, or less than 25 minutes, or less than 20 minutes.

The present invention can be further defined as the time to maximumplasma concentration. In one embodiment the time to maximum plasmaconcentration is less than 35 minutes, or less than 30 minutes or lessthan 25 minutes.

The composition of the present invention contains an intragranularportion and an extragranular portion. The intragranular portion maycontain naproxen sodium, compression fillers, binders and disintegrants.Compressible fillers include but are not limited to microcrystallinecellulose, directly compressible microcrystalline cellulose, celluloses,water insoluble celluloses, starch, cornstarch and modified starches.Suitable fillers include but are not limited to starch and modifiedstarches. The filler may be added at a range of about 5 percent to about50 percent, or from about 10 percent to about 40 percent by weight ofthe tablet. Suitable disintegrants include, but are not limited to,sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linkedcarboxymethylcellulose, starches, microcrystalline cellulose, andmixtures thereof. Disintegrants may be added at a range from about 0.5percent to about 15 percent, or from about 1 percent to about 10 percentby weight of the tablet. In one embodiment the disintegrant is added inthe intragranular portion at a range of from about 1 percent to about 3percent and in the extragranular portion at a range from about 5 percentto about 9 percent by total weight of the tablet.

Extragranular materials include carbonates, compression fillers,lubricants, flow aids, and disintegrants. Suitable carbonates includepotassium bicarbonate and sodium bicarbonate. Suitable lubricantsinclude magnesium stearate and stearic acid. The lubricant or flow aidmay be added at a range of from about 0.1 percent to about 5.0 percent,of from about 0.1 percent to about 2.0 percent by weight of the tablet.Suitable flow aids include silicon dioxide. In certain embodiments, thetablet comprises less than 0.75 percent magnesium stearate, or less than0.5 percent magnesium stearate. In one embodiment the compression fillerin the extragranular portion is microcrystalline cellulose. In thisembodiment the microcrystalline cellulose has a mean particle size ofless than 50 microns, or less than 30 microns.

In one embodiment the extrangraular portion comprises a “pH modulatingagent” and includes one or more than one pH modulating agents whichalter the pH of an aqueous solution. These may include acids, bases or acombination of one or more acids and/or bases.

The carbonate may be any pharmaceutically acceptable soluble carbonateor a mixture thereof and includes bicarbonate. Reference to a“bicarbonate” or a “carbonate” includes a single agent or multiple (i.e.two or more) agents. Preferred carbonates include but are not limited tosodium bicarbonate, sodium carbonate, potassium bicarbonate, potassiumcarbonate, calcium bicarbonate, calcium carbonate, magnesiumbicarbonate, magnesium carbonate, ammonium bicarbonate, ammoniumcarbonate, sodium glycine carbonate, disodium glycine carbonate,arginine carbonate, lysine carbonate and/or other pharmaceuticallyacceptable carbonates or homologs or functional equivalents thereof andcombinations thereof. The carbonate may be added at a range of fromabout 20 percent to about 50 percent, or from about 25 percent to about45 percent by weight of the tablet. In one embodiment the intragranularportion is substantially free of the carbonate. By substantially free,as used herein, the intragranular portion comprises less than 0.1percent of carbonate by weight of the tablet.

The carbonates of the present invention have a mean particle size rangeof from about 50 microns to about 200 microns, or from about 75 micronsto about 100 microns. The particle size of the carbonate portion of thepresent invention contributes to the dissolution of the composition. Itwas found that the higher the particle size of the carbonate, the slowerthe dissolution profile of the composition.

The intragranular portion of the present invention also comprisesphysical characteristics which contribute to the dissolution of thecomposition. In one embodiment the mean particle size of theintragranular portion is from about 200 microns to about 400 microns, orfrom about 200 microns to about 300 microns.

Naproxen sodium has pH related solubility. In pH above 5.4, naproxensodium stays in solution. At lower acidic pH, naproxen sodium dissolvesbut immediately precipitates out into a fine colloidal particulatematter. If the naproxen precipiates in the stomach, the naproxen mustpass into the small intestine before it re-dissolves creating a delay inabsorption. The particle size of the intragranular and carbonateportions of the invention help keep the active ingredient naproxen insolution as it dissolves in the acidic pH of the stomach. The carbonateportion of the dosage form dissolves at a rate such that it raises thepH of the milieu in the micro and macro environment of the stomach whichfacilitates the dissolution of naproxen and allows the naproxen toremain in solution and allows absorption of naproxen to begin in thestomach.

In certain embodiments bulk density of the intragranular portion is fromabout 0.5 to about 0.9 g/cc, or from about 0.5 to about 0.7 g/cc. Incertain embodiments, the tablet of the present invention is compressedat specific compression force ranges, including from about 18kilonewtons to about 26 kilonewtons, for a hardness of from about 10kiloponds to about 17 kiloponds. In embodiments where 300 mg ofbicarbonate is incorporated into the tablet blend, the tablet comprisesa hardness of about 10 kiloponds to about 16 kiloponds. In embodimentswhere 500 mg of carbonate is used, the tablet comprises a hardness ofabout 11 kiloponds to about 17 kiloponds.

Hardness is a term used in the art to describe the diametral breakingstrength as measured by conventional pharmaceutical hardness testingequipment, such as a Schleuniger Hardness Tester. In order to comparevalues across different size tablets, the breaking strength must benormalized for the area of the break. This normalized value, expressedin kp/cm2, is sometimes referred in the art as tablet tensile strength.A general discussion of tablet hardness testing is found in Leiberman etal., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2.sup.nd ed., MarcelDekker Inc., 1990, pp. 213-217, 327-329.

In other embodiments the tablets of the present invention disintegratein water. In this case the disintegration time is measured using theDisintegration test and apparatus in USP 28, Section 701 using deionizedwater at 37° C. The disintegration time for tablets of the presentinvention are less than 3 minutes, or less than 2 minutes and 30seconds. In other embodiments the granulation (intragranular portion) isgranulated and passed as a wet material through a mill prior to drying.In other embodiments, the dosage form may be a tablet, capsule, powderor other unit presentation. These dosage forms may also comprise anintragranular and extragranular portion.

Preferably, the carbonate is present in an amount from about 1% to about75% by weight of swallow formulation and in an amount that willneutralise between about 0.01 and 10 millimoles of hydrochloric acid.More preferably the carbonate is present in an amount from about 10% toabout 70% by weight in the swallow formulation and in an amount thatwill neutralise between about 0.02 and 8 millimoles of hydrochloricacid. The carbonate component of the pH modulating agent is present inan amount from about 1 mg to about 500 mg in the swallow formulation, orfrom about 300 mg to 500 mg. Examples of other particular amounts ofcarbonate include 8 to 850 mg per swallow formulation. More preferablythe carbonate is present in an amount from about 15 mg to 700 mg.

In one swallow formulation embodiment, the carbonate is sodiumbicarbonate and/or potassium bicarbonate and is present in an amountfrom about 5% to 75% by weight of the swallow formulation.

The water uptake agent may be present in an amount from 5% to 95%, or10% to 90% or more preferably from 20% to 60% by weight of the swallowformulation and more preferably between 30% and 50% by weight of theswallow formulation.

Preferably, the ratio of water uptake agent to pH modulating agent isbetween 0.1:1 and 20:1. More preferably the ratio of water uptake agentto pH modulating agent is between 0.3:1 and 15:1 or even more preferablybetween 0.5:1 and 8:1 by weight.

Typically, at least 50% of the therapeutic compound is dissolved fromthe swallow formulation within 300 seconds in USP dissolution apparatus2 with 900 mL 0.0033 N hydrochloric acid at 30 rpm and 37° C. In apreferred embodiment at least 55% of the therapeutic compound isdissolved from the swallow formulation within 300 seconds in USPdissolution apparatus 2 with 900 mL 0.0033 N hydrochloric acid at 30 rpmand 37° C. In another embodiment, at least 50% is dissolved in 240seconds. In another embodiment, at least 75% is dissolved from theswallow formulation within 180 seconds in USP dissolution apparatus 2with 900 mL of pH 7.4 phosphate buffer at 50 rpm and 37° C. In apreferred embodiment at least 95% is released within 300 seconds in USPdissolution apparatus 2 with 900 mL of pH 7.4 phosphate buffer at 50 rpmand 37° C.

Example 1: Protocol for Naproxen Pharmacokinetic (PK) EvaluationMethodology:

This study which was conducted was an open-label, single-dose,randomized, crossover study design conducted in three parts and fiveseparate treatment periods. Thirty healthy subjects, ages 18 to 55 yearswere enrolled. No less than approximately 40% of either gender wererepresented in the study population.

Part 1 of the study was a fasted, three-way crossover design in whichall subjects were randomized to six sequences of Treatments A, B and Cover consecutive periods, combined with one of treatments D and E inPart 2, and one of treatments F, G and H in part 3.

In Part 1, the treatments consisted of a single dose of naproxen sodiumas test 220 mg tablet formulation 1 (Treatment A), test 220 mg tabletformulation 2 (Treatment B) and Aleve® 220 mg tablet (Treatment C), thatwere administered with approximately 240 mL water after an overnightfast of at least 10 hours.

In Part 2, the treatments were a single dose of naproxen sodium asNalgesin S® 275 mg tablet (Treatment D) or Aleve 220 mg Liquid Gels®(Treatment E). In Part 3, the treatments were a single dose of naproxen25 sodium as test 220 mg tablet formulation 1 (Treatment F), test 220 mgtablet formulation 2 (Treatment G), or Aleve® 220 mg tablet (TreatmentH) approximately 30 minutes after the start of a high-fat breakfast. Thedose was swallowed with approximately 240 mL water.

A washout period of at least 6 days separated the treatmentadministration. In each study period, 17 blood samples forpharmacokinetic analysis were taken within 1 hour before and at 5, 10,20, 40, 60, 80, 100 minutes, as well as at 2, 3, 4, 6, 8, 12, and 24,36, and 48 hours after drug administration. Plasma was harvested andquantified for naproxen using a validated analytical method. Subjectswere monitored to report any adverse events that may occur.

Objectives:

Part 1. To compare the bioavailability of naproxen sodium from singledoses of:

-   -   test 220 mg tablet formulation 1 relative to Aleve® 220 mg        tablet in a fasted state;    -   test 220 mg tablet formulation 1 relative to test 220 mg tablet        formulation 2 in a fasted state; and    -   test 220 mg tablet formulation 2 relative to Aleve® 220 mg        tablet in a fasted state.

Part 2. To compare bioavailability of naproxen sodium from single doseof:

-   -   test 220 mg tablet formulation 1 relative to reference products        (Nalgesin S® 275 mg tablet and Aleve 220 mg Liquid Gels®) in a        fasted state; and    -   test 220 mg tablet formulation 2 relative to reference products        (Nalgesin S® 275 mg tablet and Aleve 220 mg Liquid Gels®) in a        fasted state.

Part 3. To assess potential food effects by comparing thebioavailability of naproxen sodium from single doses of:

-   -   test 220 mg tablet formulation 1 in a fed state relative to test        220 mg tablet formulation 2 in a fed state;    -   test 220 mg tablet formulation 1 in a fed state relative to        Aleve® 220 mg tablet in a fed state; and    -   test 220 mg tablet formulation 2 in a fed state relative to        Aleve® 220 mg tablet in a fed state.

Test products, dosage, and mode of administration:

-   -   one naproxen sodium test 220 mg tablet, formulation 1, was        administered orally with approximately 240 mL water in a fasted        state (Treatment A)    -   one naproxen sodium test 220 mg tablet formulation 2, was        administered orally with approximately 240 mL water in a fasted        state (Treatment B)    -   one naproxen sodium test 220 mg tablet, formulation 1, was        administered orally with approximately 240 mL water in a fed        state (Treatment F)    -   one naproxen sodium test 220 mg tablet formulation 2, was        administered orally with approximately 240 mL water in a fed        state (Treatment G)

Reference product, dosage, and mode of administration:

-   -   one Aleve® 220 mg tablet was administered orally with        approximately 240 mL water in a fasted state (Treatment C)    -   one Nalgesin S® 275 mg tablet was administered orally with        approximately 240 mL water in a fasted state (Treatment D)    -   one Aleve 220 mg Liquid Gel® capsule was administered orally        with approximately 240 mL water in fasted state (Treatment E)    -   one Aleve® 220 mg tablet was administered orally with        approximately 240 mL water in a fed state (Treatment H)

Duration of Study: The study duration was about nine weeks, whichincludes duration for eligibility screening (between one and 28 daysbefore first dose administration) and five separate treatment periods.Subjects remained at the study site for the duration of each treatmentperiod.

Data Evaluation: Pharmacokinetic:

The following pharmacokinetic (PK) parameters were determined by meansof non-compartmental analysis for each subject and treatment: Cmax(maximum plasma concentration), Tmax (time to maximum concentration),and plasma naproxen concentrations at 5, 10, 20, 40, 60, and 80 minutes(Cp5 MIN Cp10 MIN, Cp20 MIN, Cp40 MIN, Cp60 MIN and Cp80 MIN), λZ (rateconstant) and T_(half) (half life).

Statistical Methods

The proposed sample size calculations are for part 1 of the study.Assuming an intra-subject coefficient of variation (CV) of 13% for CMAX,a sample size of 30 subjects were provided at least 90% power to ensurethe two-sided 90% confidence interval for the ratio will be between80-125% of the reference product, should the true mean ratio of Test toReference product be between 0.89 and 1.12. The estimate of 13%intra-subject CV was observed in previous Naproxen bioequivalence study.See Product monograph ALEVE Liquid Gels Naproxen Sodium Tablets USP 220mg Non-steroidal anti-inflammatory drug Analgesic, Antipyretic, BayerInc. Consumer Care, Apr. 10, 2013. Control No. 162299; and Setiawati etal., Bioequivalence Study with Two Naproxen Sodium Tablet Formulationsin Health Subjects, Journal of Bioequivalence & Bioavailability, 1(1):28-33 (2009).

Analysis for Cmax, as well as the naproxen plasma concentrations at 40,60 and 80 minutes (Cp_(40 min), Cp_(60 min), and Cp_(80 min)) were asfollows:

Statistical comparisons of pairs of treatment (A versus B, A versus C, Bversus C) were based on log transformed (natural log) pharmacokineticparameter data. A mixed-effect analysis of variance model that includestreatment, period, and treatment sequence as fixed effects, and subjectwithin sequence as a random effect, were used to estimate the leastsquares means and intra-subject variance. Model-based 90% confidenceintervals for the geometric mean ratio of Cmax corresponding to thereference.

Analysis of Plasma Samples

During each study period, blood samples (4 mL) for pharmacokineticanalysis were collected into appropriately labeled K2EDTA vacutainer®blood collection tubes. The tube labels included the followinginformation (at a minimum): protocol number, subject identificationnumber, sampling time, study period, and any applicable site specificsample identification code.

Blood samples were collected before dosing (predose) and at specifictimes following each designated dose. The pharmacokinetic samples werecollected at the exact nominal time relative to dosing. Samplescollected outside of 1-minute window for postdose time points up to 60minutes or outside of 2-minute window for time points after 60 minuteswill be captured as protocol deviations. The exact time of the samplecollection were noted on the source document and data collection tool(e.g. CRF).

After drawing the blood, the tube was gently inverted approximatelyeight times after collection and immediately placed in an ice bath fortransport to a centrifuge. Samples were kept on ice and processed intoplasma within 90 minutes. Any deviations regarding the pharmacokineticblood sample and handling process were recorded on the appropriate log.

Samples were centrifuged at high speed (˜1500 g revolutions per minute)for approximately 10 minutes at approximately 4° C. nominal. As soon asthe centrifuge stops, the samples were returned to an ice bath. Plasmawas withdrawn into two equally divided aliquots in an appropriatelylabeled polypropylene transfer tube (polypropylene push-cap tube) (whichcan hold approximately 5 mL plasma). The tubes were labeled withfreezer-safe labels and/or marked by permanent marker, and the labelswere filled out and affixed to the tube before placing plasma into thetube.

Samples were placed in the freezer (approximately −20° C. nominal)within 90 minutes from the time of collection and stored until shipped.The time samples were placed in the freezer will be recorded in a sampleaccountability record. Samples were analyzed using a validatedanalytical method in compliance with the standard operating proceduresof the bioanalytical laboratory. The range of validated method was 0.5μg/mL to 100.000 μg/mL.

Model for Analysis of Results

The following single-dose pharmacokinetic parameters for naproxen sodiumin plasma were estimated using noncompartmental methods:

-   -   Plasma concentrations measured at 5, 10, 20, 40, 60 and 80        minutes (Cp5 MIN Cp10 MIN, Cp20 MIN, Cp40 MIN, Cp60 MIN and Cp80        MIN) after dose administration;    -   Maximum plasma concentration (Cmax);    -   Time to maximum concentration (Tmax);    -   Half-life (T½);    -   Elimination rate constant (λz)

Cmax parameters for Nalgesin S® 275 mg tablet (E) were presented withdose normalized and without dose normalized data.

Model for Analysis of Fasted and Fed States

Comparisons were assessed of potential food effects by comparing thebioavailability of naproxen sodium from single doses of:

-   -   test 220 mg tablet formulation 1(A) fasted state versus test 220        mg tablet formulation 1(F) fed state    -   test 220 mg tablet formulation 2 (B) fasted state versus test        220 mg tablet formulation 2(G) fed state    -   Aleve® 220 mg tablet (C) in a fasted state versus Aleve® 220 mg        tablet (H) in a fed state    -   test 220 mg tablet formulation 1(F) fed state versus test 220 mg        tablet formulation 2(G) fed state    -   test 220 mg tablet formulation 2(G) fed state versus Aleve® 220        mg tablet (H) in a fed state    -   test 220 mg tablet formulation 1(F) fed state versus Aleve® 220        mg tablet (H) in a fed state

Statistical comparisons of pairs of treatment fed versus fasted states(F versus A, G versus B, H versus C) for set 1 PK parameters wereanalyzed using paired t test for log transformed (natural log)pharmacokinetic parameter. 90% confidence intervals for the geometricmean ratio of Cmax corresponding to the reference treatment (F versus A,G versus B, H versus C) will be calculated in each case.

Example 2: PK and Bioequivalence Results

TABLE 1 Mean PK Parameters for Naproxen Under Fasted Condition Cp 5 Cp10Cp20 T_(max) Cmax min min min (h)^(a) Formulation 1 50.69 6.32 21.9 44.50.33 (300 mg (16.7) (135.9) (81) (39.5) (0.17-2.00) Sod. Bicarb) (n =29) Formulation 2 54.1 3.69* 22.41 47.16 0.33 (500 mg (16.5) (138.4)(76) (36.2) (0.17-1.00) Sod. Bicarb) (n = 27) Aleve 45.16 0.75 6.3627.11 0.67 (n = 27) (17.6) (115.7) (78.2) (47.7) (0.67-3.00) Aleve LG42.31 0.48 4.73 13.43 1 (n = 14) (26.8) (177.4) (335.6) (110.2)(0.20-12.00) Nalgesin S 53.54 2.17 7.86 27.24 0.83 (n = 14) (14.3)(163.1) (91.8) (51.3) (0.67-1.67) *w.r.t. Formulation 1 (p < 0.05). Allearly absorption parameters were statistically (p < 0.05) significantlydifferent for both Formulation 1 and Formulation 2 compared to Aleve,Aleve LG and Nalgesin under fasted condition

TABLE 2 Mean PK Parameters for Naproxen Under Fed Condition Cmax Cp_(20 min) Cp _(40 min) Cp _(60 min) T_(max) (h)^(a) Formulation 1 31.814.29*, † 18.27 21.85 3* (300 mg (11.6) (60.5) (54.2) (46.8) (0.67-4)Sod. Bicarb) (n = 9) Formulation 2 28.91 17.49*, † 23.02 24.55 1.83*(500 mg (17.5) (51) (36.6) (30.4) (1.00-6.00) Sod. Bicarb) (n = 8)Aleve ® 34.67 5.12* 11.32 15.76 2.5* (n = 10) (16.3) (127.8) (118)(85.6) (0.67-4.00) *w.r.t. Fasted, † w.r.t. Aleve under Fed p < 0.05

TABLE 3 Mean PK Parameters for Naproxen Under Fasted Condition CmaxCp_(5 MIN) Cp_(10 MIN) Cp_(20 MIN) Cp_(40 MIN) Cp_(60 MIN) Cp_(80 MIN)(ug/mL) (ug * h/mL) (ug * h/mL) (ug * h/mL) (ug * h/mL) (ug * h/mL)(ug * h/mL) T_(max) (h) ^(a) Formulation 50.69 6.324 21.982 44.45542.521 39.578 36.95 0.33 1 (300 mg (16.7) (135.9) (81)    (39.5) (19.1)(14.5) (12.6)  (0.17-2.00) Sod. Bicarb) (n = 29) Formulation 54.1 3.6922.41  47.16 46.25 40.78 37.15 0.33 1 (500 mg (16.5) (138.4) (76)   (36.2) (14.1) (10.6) (11.8)  (0.17-2.00) Sod. Bicarb) (n = 27) Aleve45.16 0.75 6.36 27.11 40.84 39.48 38.09 0.33 (n = 27) (17.6) (115.7)(78.2)  (47.7) (29.5) (21.4) (18.6)  (0.17-1.00) Aleve Liquid 42.31 0.484.73 13.43 34.43 34.75 34.98 0.67 Gel (n = 14) (26.8) (177.4) (335.6)  (110.2) (45.7) (39.3) (34.8)  (0.67-3.00) Nalgesin S 53.54 2.17 7.8627.24 47.74 48.5 47.1  0.67 (n = 14) (14.3) (163.1) (91.8)  (51.3)(28.2) (19.6) (13)   (0.17-1.00)

TABLE 4 Summary of Time to Effective Blood Plasma Concentration Time to15-20 Tmax, Cmax μg/mL* (min) (min) (μg/mL) Fasted** Fed*** Fasted FedFasted Fed Formulation 1 (300 mg 7-9 20-50 20 180 50.7 31.8 Sod Bicarb)Formulation 2 (500 mg 7-9 15-25 20 110 54.1 28.9 Sod Bicarb) Aleve (220mg 14-17 60-85 40 150 45.2 34.7 Naproxen) Aleve LG (220 mg 20-24 60 42.3Naproxen Nalgesin S 275 13-17 50 53.5 Sod Bicarb: Sodium Bicarbonate*15-20 μg/mL is considered the minimum effective blood plasmaconcentration for naproxen **FIG. 1 ***FIG. 2

Example 3: Compositions for Use in PK Study

The following formulations were prepared for use in the PK study.

TABLE 5 220 mg Naproxen Sodium, 300 mg Sodium Bicarbonate formulation(Formulation 1) Weight % Material Mg/Tablet (% w/w) IntragranularNaproxen Sodium USP 220.00 26.27 Microcrystalline Cellulose, NF (Avicel50.00 5.97 PH101)¹ Pregelatinized Starch, USP² 16.00 1.91 Povidone, USP(PVP K29/32)³ 10.00 1.19 Crospovidone, NF⁴ 16.00 1.91 Purified Water⁵ —— Extragranular Sodium Bicarbonate USP 300.00 35.83 Crospovidone NF⁴63.00 7.52 Microcrystalline Cellulose NF (Avicel 140.00 16.72 PH105)¹Colloidal Silicon Dioxide NF (Aerosil 4.00 0.48 200)⁶ Magnesium StearateNF 6.00 0.72 Tablet Coating Film Coating Solution (Polyvinyl 12.40 1.48alcohol based)⁷ Water — — TOTAL 837.40 100.00 ¹Commercially availablefrom the FMC Corporation as Avicel ® ²Commercially available from theColorcon Corporation as Starch 1500 ³Commercially available from theAshland Corporation as PVP K29/32 ⁴Commercially available from the BASFCorporation as Kollidon ® CL ⁵Water removed upon drying granulation⁶Commercially available from the Evonik Corporation as Aerosil ®⁷Commercially available from the Colorcon Corporation as Opadry ® II

Granulation and Tableting Procedure (for Formulation 1 (Table 5) &Formulation 2 (Table 6)):

-   -   1. The intragranular material was added to a high shear        granulator; the purified water was added.    -   2. The granulation was discharged from the granulator and passed        through a Co-Mil for sizing and added to a fluid bed dryer.    -   3. The granulation was dried and again passed through a Co-Mil;        and blended with the extragranular materials to form a final        blend.    -   4. The blend was compressed into tablets at a compression force        of 18-26 kilonewtons, resulting in a hardness of 10-15        kiloponds.    -   5. The tablets were added to a coating pan.    -   6. The film coating solution was sprayed onto the tablets and        dried.

Physical Parameters for Intragranular Portion & Sodium Bicarbonate

-   -   Bulk Density of intragranular (granulation) portion: 0.6        g/cc±0.05    -   Tap Density of intragranular (granulation) portion: 0.7        g/cc±0.15    -   Particle Size Distribution of intragranular (granulation) via        sieve analysis: 222-372 μm    -   Particle Size of Sodium Bicarbonate USP: 90-95 μm

TABLE 6 220 mg Naproxen Sodium, 500 mg Sodium Bicarbonate formulation(Formulation 1) Weight % Material Mg/Tablet (% w/w) IntragranularNaproxen Sodium USP 220.00 20.45 Microcrystalline Cellulose, NF (Avicel50.00 4.65 PH101)¹ Pregelatinized Starch, USP² 16.00 1.49 Povidone, USP(PVP K29/32)³ 10.00 0.93 Crospovidone, NF⁴ 16.00 1.49 Purified Water⁵ —— Extragranular Sodium Bicarbonate USP 500.00 46.47 Crospovidone NF⁴80.00 7.43 Microcrystalline Cellulose NF (Avicel 154.00 14.31 PH105)¹Colloidal Silicon Dioxide NF (Aerosil 6.00 0.56 200)⁶ Magnesium StearateNF 8.00 0.74 Tablet Coating Film Coating Solution (Polyvinyl alcohol15.90 1.48 based)⁷ Water⁵ — — TOTAL 1075.90 100.00 ¹Commerciallyavailable from the FMC Corporation as Avicel ® ²Commercially availablefrom the Colorcon Corporation as Starch 1500 ³Commercially availablefrom the Ashland Corporation as PVP K29/32 ⁴Commercially available fromthe BASF Corporation as Kollidon ® CL ⁵Water removed upon dryinggranulation and coating ⁶Commercially available from the EvonikCorporation as Aerosil ® ⁷Commercially available from the ColorconCorporation as Opadry ® II

Example 3: Dissolution (In-Vitro) Results

The formulations in Table 8 were tested for dissolution using a USPdissolution apparatus 2 with 900 mL of 0.0033 N hydrochloric acid at 30rpm and 37° C. Samples were pulled at respective timepoints and analyzedvia a high pressure liquid chromatography (HPLC) apparatus equipped witha Phenomenex Kinetex C18 column (50 mm×4.6 mm); with a mobile phase of60:40 Water: Methanol plus 0.1% trifluoroacetic acid; a flow rate of 1.0mL/min; an injection volume of 10 μL; a UV detector set at 332 nm; and acolumn temperature of 30° C.

TABLE 7 Dissolution in 0.0033M HCL Dissolution (% released, Average of n= 6 vessels) Media: 0.0033M HCl, 30 RPM, USP Apparatus 2 (paddles)Formulation 0 Min 5 Min 10 Min 30 Min Formulation 1 0 57 82 91 (300 mgSod Bicarb) Formulation 2 0 61 80 90 (500 mg Sod Bicarb) Aleve 0 14 23227 (220 mg Naproxen) Aleve LG* 0 1 3 5 (220 mg Naproxen) Nalgesin S 2750 9 14 22 Min = Minutes LG = Liquigel

The formulations in Table 8 were also tested for dissolution using a USPdissolution apparatus 2 with 900 mL of 7.4 phosphate buffer at 50 rpmand 37° C. The data is shown in Table 12. The dissolution method (media,apparatus, speed, temperature) was the same as for naproxen sodiumtablets as defined by USP 41-NF 36, The method for analyzing the pulleddissolution samples was the same as those for Table 11.

TABLE 8 Dissolution in pH 7.4 phosphate buffer Dissolution (% released,Average of n = 6 vessels) Media: 7.4 Buffer, 30 RPM, USP Apparatus 2(paddles) Formulation 3 Min 5 Min 6 Min 10 Min 30 Min 45 Min 60 MinFormulation 1 (300 mg Sod 92 100 101 101 101 Bicarb) Aleve (220 mgNaproxen) 12.5 26.4 58.2 95.1 98.9 Aleve LG* (220 mg 2 3 12 62 80 97Naproxen Min = Minutes LG = Liquigel

1.-14. (canceled)
 15. A method for the treatment of pain, which methodcomprises administering to a fasted subject in need thereof, animmediate release naproxen sodium formulation so that the blood plasmaconcentration levels of naproxen range from and include at least 15-20μg/ml in 10 minutes or less.
 16. A method for the treatment of painaccording to claim 15 wherein the immediate release naproxen sodiumformulation provides a blood plasma naproxen concentration of at least15-20 μg/ml in 7-9 minutes.
 17. A method for the treatment of painaccording to claim 15 wherein the formulation comprises an effectiveamount of naproxen, salts thereof and combinations thereof and a solublecarbonate, and wherein the particle size of the soluble carbonate isfrom about 50 microns to 200 microns.
 18. A method for the treatment ofpain according to claim 17 wherein the particle size of the carbonate isfrom about 75 microns to 100 microns.
 19. A method for the treatment ofpain according to claim 17 wherein the amount of carbonate in theformulation is from about 300 mg to 500 mg.
 20. A method for thetreatment of pain according to claim 15 wherein the formulationcomprises an effective amount of naproxen, salts thereof andcombinations thereof, and an intragranular portion comprisingcompression filler, binder and disintegrant, and wherein the particlesize of the intragranular portion is from about 200 microns to 400microns.
 21. A method for the treatment of pain according to claim 20wherein the particle size of the intragranular portion is from about 200microns to 300 microns.
 22. A method for the treatment of pain, whichmethod comprises administering to a fed subject in need thereof, animmediate release naproxen sodium formulation so that the blood plasmaconcentration levels of naproxen range from and include at least 15-20μg/ml in 50 minutes or less.
 23. A method for the treatment of painaccording to claim 22 wherein the immediate release naproxen sodiumformulation provides a blood plasma concentration level of naproxen thatranges from and includes at least 15-20 μg/ml in 25 minutes or less. 24.A method for the treatment of pain according to claim 22 wherein theformulation comprises an effective amount of naproxen, salts thereof andcombinations thereof and a soluble carbonate, and wherein the particlesize of the soluble carbonate is from about 50 microns to 200 microns.25. A method for the treatment of pain according to claim 24 wherein theparticle size of the carbonate is from about 75 microns to 100 microns.26. A method for the treatment of pain according to claim 24 wherein theamount of carbonate in the formulation is from about 300 mg to 500 mg.27. A method for the treatment of pain according to claim 22 wherein theformulation comprises an effective amount of naproxen, salts thereof andcombinations thereof, and an intragranular portion comprisingcompression filler, binder and disintegrant, and wherein the particlesize of the intragranular portion is from about 200 microns to 400microns.
 28. A method for the treatment of pain according to claim 27wherein the particle size of the intragranular portion is from about 200microns to 300 microns.
 29. An immediate release solid dosage formcomprising an effective amount of naproxen, salts thereof andcombinations thereof, and a soluble carbonate, wherein the particle sizeof the soluble carbonate is from about 50 microns to 200 microns. 30.The immediate release solid dosage form of claim 29 wherein the solublecarbonate is selected from the group consisting of sodium carbonate,sodium bicarbonate, calcium carbonate, magnesium carbonate, ammoniumcarbonate, ammonium bicarbonate, potassium bicarbonate, sodium glycinecarbonate, disodium glycine carbonate, arginine carbonate and lysinecarbonate.
 31. The immediate release solid dosage form of claim 29 or 30wherein the particle size of the soluble carbonate is from about 75microns to 100 microns.
 32. The immediate release solid dosage form ofclaim 29 wherein the amount of soluble carbonate present in the dosageform is from about 300 mg to 500 mg.
 33. The immediate release soliddosage form of claim 29 wherein at least 50% of the naproxen isdissolved from the immediate release solid dosage form within 300seconds in USP dissolution apparatus 2 with 900 mL 0.0033 N hydrochloricacid at rpm and 37° C.
 34. The immediate release solid dosage form ofclaim 29 wherein at least 50% of the naproxen is dissolved from theimmediate release solid dosage form within 300 seconds in USPdissolution apparatus 2 with 900 mL of pH 7.4 phosphate buffer at rpmand 37° C.
 35. The immediate release solid dosage form of claim 29wherein at least 75% of the naproxen is dissolved from the immediaterelease solid dosage form within 600 seconds in USP dissolutionapparatus 2 with 900 mL of pH 7.4 phosphate buffer at rpm and 37° C. 36.The immediate release solid dosage form of claim 29 further comprisingan intragranular portion comprising compression filler, binder anddisintegrant, wherein the particle size of the intragranular portion isfrom about 200 microns to 400 microns.
 37. The immediate release soliddosage form of claim 34 wherein the particle size of the intragranularportion is from about 200 microns to 300 microns.
 38. The immediaterelease solid dosage form of claim 34 wherein the bulk density of theintragranular portion is from about 0.5 g/cc to about 0.9 g/cc.
 39. Theimmediate release solid dosage form of claim 29 wherein the dosage formhas a hardness of from about 10 kiloponds to about 17 kiloponds.